Tumor necrosis factor α, or TNF-α, is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. When administered to animals or humans, it can cause inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNF-α production thus has been implicated in a number of disease conditions. These disease conditions include endotoxemia and/or toxic shock syndrome (Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)); rheumatoid arthritis, Crohn's disease, cachexia (Dezube et al., Lancet, 335(8690), 662 (1990)) and Adult Respiratory Distress Syndrome (ARDS) where TNF-α concentration in excess of 12,000 pg/mL have been detected in pulmonary aspirates from ARDS patients (Millar et al., Lancet 2(8665), 712-714 (1989)). Systemic infusion of recombinant TNF-α also resulted in changes typically seen in ARDS (Ferrai-Baliviera et al., Arch. Surg. 124(12), 1400-1405 (1989)). Certain 2-(1-phenylethyl)isoindolin-1-one compounds have been shown to reduce levels of TNF-α in the literature such as U.S. Pat. Nos. 6,667,316 and 6,020,358 and U.S. Patent Publication Nos. 2004/0254214 and 2004/0204448, all of which are incorporated herein by reference in their entirety.
Existing methods for synthesizing 2-(1-phenylethyl)isoindolin-1-one compounds have been described in U.S. Pat. Nos. 6,667,316 and 6,020,358 and U.S. Patent Publication Nos. 2004/0254214 and 2004/0204448. While these methods are useful for preparing 2-(1-phenylethyl)isoindolin-1-one compounds, alternative methods for the preparation of 2-(1-phenylethyl)isoindolin-1-one compounds, particularly for manufacturing scale production, are desirable.
Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.